title: Aberrations of EZH2 in cancer.
abstract: Control of gene expression is exerted at a number of different levels, one of which is the accessibility of genes and their controlling elements to the transcriptional machinery. Accessibility is dictated broadly by the degree of chromatin compaction, which is influenced in part by polycomb group proteins. EZH2, together with SUZ12 and EED, forms the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3). PRC2 may recruit other polycomb complexes, DNA methyltransferases, and histone deacetylases, resulting in additional transcriptional repressive marks and chromatin compaction at key developmental loci. Overexpression of EZH2 is a marker of advanced and metastatic disease in many solid tumors, including prostate and breast cancer. Mutation of EZH2 Y641 is described in lymphoma and results in enhanced activity, whereas inactivating mutations are seen in poor prognosis myeloid neoplasms. No histone demethylating agents are currently available for treatment of patients, but 3-deazaneplanocin (DZNep) reduces EZH2 levels and H3K27 trimethylation, resulting in reduced cell proliferation in breast and prostate cancer cells in vitro. Furthermore, synergistic effects are seen for combined treatment with DNA demethylating agents and histone deacetylation inhibitors, opening up the possibility of refined epigenetic treatments in the future.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury, and Human Genetics Division, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chase
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2